During virus infection, interferon-alpha induces the dsRNA-dependent antiviral enzyme 2'5'-oligoadenylate synthetase (2'5'AS), which in turn activates latent ribonuclease (RNAseL) leading to degradation of viral RNA. It has been shown that dsRNA can also activate this pathway in the absence of virus infection. In 4 different studies, we have previously shown that basal 2'5'AS activity is significantly elevated in patients with Type 1 (insulin-dependent) diabetes. Type 1 diabetes results from autoimmune destruction of the insulin-producing pancreatic beta cells. Genetic factors are known to be involved but the non-genetic factors, which initiate autoimmunity are unclear. We hypothesize that increased 2'5'AS activity is detrimental to pancreatic beta cells (RNAseL also degrades celluar RNA) and may reflect chronic or repeated virus infection (which could also damage beta cells). The resulting minor but repeated death of beta cells would provide the antigenic stimulus for full-blown autoimmune attack leading to destruction of the beta cell mass and onset of clinical diabetes. Thus, elevated 2'5'AS activity, with or without virus infection, could be important in the etiology of this disease. The observations of increased 2'5'AS activity in Type 1 diabetics are novel and need to be further investigated. Understanding the mechanism of elevated 2'5'AS might suggest new approaches to preventing Type 1 diabetes. The aim of the proposed study is to determine: 1) whether 2'5'AS activity becomes increased prior to the onset of diabetes, 2) if so, when, and 3) the relationship between elevated activity and evidence for virus infection during the preclinical phase. To accomplish these aims, 2'5'AS activity will be measured in Finnish children prospectively studied since birth for presence of multiple beta cell autoantibodies (markers of beta cell damage and indicative of high risk for developing diabetes). The temporal association between antiviral 2'5'AS activity, virus infection, antiviral antibodies or RNA, beta cell autoantibodies, and development of diabetes will be examined by analyzing 2'5'AS activity in 50 children with autoantibodies (high risk of developing diabetes) and 50 children without autoantibodies (low risk of diabetes). In ancillary studies of 83 Danish families, we will determine which isoform of 2'5'AS is increased in diabetic individuals, and assess the possibility that 2'5'AS activity is influenced by genes in the antiviral system.